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Molecular and Cellular Biology, September 1998, p. 5166-5177, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of the Gamma Interferon (IFN-gamma ) Promoter and Subsequent Downregulation of IFN-gamma Production

Judy A. Mikovits,1,* Howard A. Young,2 Paula Vertino,3 Jean-Pierre J. Issa,3 Paula M. Pitha,3 Susan Turcoski-Corrales,4 Dennis D. Taub,5 Cari L. Petrow,1 Stephen B. Baylin,3 and Francis W. Ruscetti6

Intramural Research Support Program, SAIC Frederick,1 and Laboratory of Experimental Immunology2 and Laboratory of Leukocyte Biology,6 Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick Maryland 21702-1201; Oncology Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 212313; CBER, Rockville, Maryland 208924; and Laboratory of Immunology, National Institute of Aging, Baltimore, Maryland 212245

Received 3 March 1998/Returned for modification 28 April 1998/Accepted 23 June 1998

The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including interleukin-12, tumor necrosis factor alpha, and gamma interferon (IFN-gamma ), following human retrovirus infection is well documented. One process by which such gene expression may be modulated is altered DNA methylation. In subsets of T-helper cells, the expression of IFN-gamma , a cytokine important to the immune response to viral infection, is regulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many possible genes whose methylation status could be affected by viral infection, we examined the IFN-gamma gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HIV-1) results in (i) increased DNA methyltransferase expression and activity, (ii) an overall increase in methylation of DNA in infected cells, and (iii) the de novo methylation of a CpG dinucleotide in the IFN-gamma gene promoter, resulting in the subsequent downregulation of expression of this cytokine. The introduction of an antisense methyltransferase construct into lymphoid cells resulted in markedly decreased methyltransferase expression, hypomethylation throughout the IFN-gamma gene, and increased IFN-gamma production, demonstrating a direct link between methyltransferase and IFN-gamma gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-gamma gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.

* Corresponding author. Mailing address: P.O. Box B, Bldg. 567, Rm. 253, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702-1201. Phone: (301) 846-5610. Fax: (301) 846-7034. E-mail: Mikovits{at}fcrfv1.ncifcrf.gov.

Molecular and Cellular Biology, September 1998, p. 5166-5177, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.